Fast dissolving tablet

ABSTRACT

The present invention relates to processes for the preparation of tablets which dissolve rapidly in the mouth and provide an excellent mouthfeel. The tablets of the invention comprise a compound which melts at about 37° C. or lower, have a low hardness, high stability and generally comprise few insoluble disintegrants which may cause a gritty or chalky sensation in the mouth. Convenient and economically feasible processes by which the tablets of the invention may be produced are also provided.

FIELD OF THE INVENTION

The current invention relates to tablets of low hardness but goodphysical stability, in particular fast dissolving tablets that can bemade at very low compression force, yet have acceptable stability, andmethods for preparing such tablets.

BACKGROUND OF THE INVENTION

Several processes are presently available by which a tablet, whichdissolves quickly in the mouth, may be formulated. However, variousdisadvantages are associated with these currently available methods forproducing fast dissolving tablets. For example the addition of highlevels of disintegrants is disclosed by Cousin et al. (U.S. Pat. No.5,464,632). Cousin et al. add two disintegrants to the disclosed tabletformulations, for example 16% starch 1500 and 13.3% crosspovidone. Theoral-disintegration time of these tablets is 35 seconds to 45 seconds.However, tablets including high levels of disintegrants have a chalky ordry feel when placed in the mouth.

Another process for producing fast dissolving tablets involves freezedrying or lyophilizing solutions or suspensions of an active ingredientand matrix forming excipients. Pebley et al. (U.S. Pat. No. 5,298,261)disclose freeze-drying a slurry or paste comprising an active ingredientand excipients placed in blister packets. Humbert-Droz et al. (WO97/36879) disclose vacuum drying, at room temperature or a slightlyelevated temperature, a suspension including the active drug, a sugaralcohol, PEG 6000, talc, sweeteners and flavors in preformed blisters.The disadvantages of the freeze drying or vacuum drying methods are time(very slow process), cost of the equipment (not done on conventionaltablet manufacturing equipment), and that it is limited to low doseactives.

Fast-dissolving tablets may also be formulated by the inclusion ofeffervescent coupled compounds. Wehling et al. (U.S. Pat. No. 5,178,878and WO 91/04757) disclose the addition of an effervescent couple (suchas sodium bicarbonate and citric acid) to a tablet. Exposure of thetablet to moisture results in contact and chemical reaction between theeffervescent couple which leads to gas production and tabletdisintegration. For this reason, tablets which include effervescentpairs are highly sensitive to moisture and have an unpleasant mouthfeel.

Tablets formed by compression under low compression force also dissolvemore rapidly than tablets formed by high compression force. However,tablets produced by these processes have a high degree of friability.Crumbling and breakage of tablets prior to ingestion may lead touncertainty as to the dosage of active ingredient per tablet.Furthermore, high friability also causes tablet breakage leading towaste during factory handling.

The present invention addresses these and other problems associated withthe prior art. The invention provides fast-dissolving tablets of lowhardness, low friability and high stability which have the addedadvantage of cost-effective methods of manufacture. In particular, thefast-dissolving tablets of the invention melt rapidly in the mouth andprovide an excellent mouth feel.

SUMMARY OF THE INVENTION

The present invention advantageously provides compositions and methodsfor preparing a fast dissolving tablet of low hardness but good physicalstability that can be made at very low compression force.

Thus, the invention provides a tablet comprising a low melting pointcompound that melts or softens at or below 37° C., a water solubleexcipient, and an active ingredient. Preferably, the low melting pointcompound comprises from about 2.5% to about 20% (wt/wt) of thecomposition (e.g., 2.5, 5, 7.5, 10, 12, 14, 16, 18, or 20% (wt/wt)).Preferably the tablet has a hardness of about 3 kP or less, morepreferably about 2 kP or less, and still more preferably about 1 kP orless. Preferably, the minimum hardness of the tablet is about 0.1 kP,although lower values, including 0.05 kP, are possible.

The invention further provides a method of producing a tabletcomposition. The method comprises combining an active agent (also termed“active ingredient” or “active”) with a fast dissolving granulation. Thefast dissolving granulation comprises a low melting point compound and awater soluble excipient. Preferably, the low melting compound is presentin an amount that will yield values of about 2.5% to about 20% (wt/wt)in a final tablet composition (e.g., 2.5, 5, 7.5, 10, 12, 14, 16, 18, or20% (wt/wt)).

The accompanying Detailed Description, Examples and Drawings furtherelaborate the invention and its advantages.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a graph of tablet hardness as a function of compressionforce for tablets of the invention prepared by a melt granulationprocess (diamonds), and tablets prepared by direct compression(squares).

FIG. 2 shows a graph of friability as a function of tablet hardness;“Number of Rotations” indicates a number of rotations in a Friabilatorwhich occur before a tablet breaks. Tablets prepared by melt granulation(diamonds) or by direct compression (squares) were evaluated.

FIG. 3 shows a graph of time of onset of disintegration (T1) as afunction of compression force for tablets of the invention (diamonds)and for tablets formed by direct compression (squares).

FIG. 4 shows a graph of disintegration time (T2) as a function ofcompression force for tablets of the invention (diamonds) and fortablets formed by direct compression (squares).

FIG. 5 shows a graph of disintegration time as a function of thefriability (as measured by the number of rotations in a Friabilatorbefore a first tablet breaks) for tablets of the invention (diamonds)and for tablets formed by direct compression (squares).

FIG. 6 shows a graph of time to dissolve (mean of disintegration time inseconds for 34 samples of a tablet of the invention (MG), two types oftablets formed by direct compression (DC1 and DC2), and a commercialfast dissolving tablet (KIDTAB®).

FIG. 7 shows a graph of grittiness score (adjusted mean determined byleast squares from ANOVA). Subjects scored this sensory attribute on ascale of 1 (low grittiness) to a 9 (high grittiness). Tablets were asdescribed for FIG. 6.

FIG. 8 shows a graph of chalkiness score (adjusted mean determined byleast squares from ANOVA). Subjects scored this sensory attribute on ascale of 1 (low chalkiness) to a 9 (high chalkiness). Tablets weredescribed for FIG. 6.

FIG. 9 shows a graph of overall preference ranking for each product (asdescribed in FIG. 6), represented by the percentage of subjects rankingeach product 1^(st), 2^(nd), 3^(rd), or 4^(th).

DETAILED DESCRIPTION

The current invention provides fast dissolving tablet formulations thatcan be formed by compression into a conventional tablet. Tabletfriability is lower than conventional fast dissolving tablets preparedby low compression. The fast dissolving tablet has at least one compoundwhich partially or fully melts or softens at or below body temperatureand a water soluble excipient. The low melting point excipient may behydrophilic or hydrophobic. The tablets of the invention may alsoinclude an active ingredient and may also include one or moredisintegrants, flavors, colorants, sweeteners, souring agents, glidantsor lubricants.

The hardness of the tablets is low (less than or equal to about 3 kP),preferably less than or equal to about 2 kP, and more preferably lessthan or equal to about 1 kP, with a minimum hardness of greater than orequal to about 0.1 kP (e.g., 0.05, 0.07, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1.0, 1.3, 1.6, 1.9, 2.0, 2.1, 2.3, 2.5, 2.7, 2.8 or 3.0kP). In a specific embodiment, hardness ranges from about 0.2 to about 1kP. Attributes such as (1) fast tablet dissolution; (2) good tabletmouth feel; and (3) good tablet physical stability are of greaterimportance than minimum and maximum values of tablet hardness.Nevertheless, the tablets are somewhat pliable, and are less fragilethan conventional tablets that have the same crushing strength. Thetablets have an excellent mouthfeel resulting from the low melting pointcomponent which melts or softens in the mouth to produce a smooth feeland masks the grittiness of insoluble ingredients. Unlike other fastdissolving tablets, the disintegration of this fast dissolving tabletoccurs by a combination of melting, disintegration of the tablet matrix,and dissolution of the water soluble excipient. Therefore, a dry feeldoes not occur. Disintegration time is 10 to 30 seconds (e.g., 10, 12,14, 16, 18, 20, 22, 24, 26, 28 or 30 seconds), depending on the tabletsize and amount of insoluble ingredients, e.g., coated active. Eventhough the tablet contains a low melting point ingredient, it isrelatively stable to high temperatures. Heating the tablet above themelting point of its low melting point component will not significantlyreduce its physical stability.

The friability of conventional tablets is measured by the percentageweight loss after atypical friability test (rotating 10 tablets in afriability apparatus for 100 rotations). This test is very harsh forconventional fast dissolving tablets and so cannot be used to measuretheir friability. Fast dissolving tablets made by direct compression atlow force crumble after a few rotations in the friability apparatus.Fast dissolving tablets manufactured by the method in the currentinvention can withstand 20-50 rotations in the friability apparatusbefore any tablet breaks. After 20 rotations, the friability (% weightlost) is typically less than 1%.

The term “low melting point compound” may include any edible compoundwhich melts or softens at or below 37° C. which is suitable forinclusion in the tablets of the invention. Materials commonly used formanufacturing suppositories usually have a melting point at or justbelow body temperature and can be used in the invention. The low meltingpoint compound can be hydrophilic or hydrophobic.

Examples of hydrophilic low-melting point compounds include, but are notlimited to, polyethylene glycol; the preferred mean molecular weightrange of polyethylene glycol for use in the tablets of the invention isfrom about 900 to about 1000. Mixtures of polyethylene glycol withdifferent molecular weights (200, 300, 400, 550, 600, 1450, 3350, 8000or 10,000) are within the scope of the invention if the mixture melts orsoftens at or below 37 degrees celcius.

Examples of hydrophobic low-melting point compounds include, but are notlimited to, low melting point triglycerides, monoglycerides anddiglycerides, semisynthetic glyceride (e.g., EUTECOL®, GELUCIRE®(gatteffosse)), hydrogenated oils, hydrogenated oil derivatives orpartially hydrogenated oils (e.g., partially hydrogenated palm kerneloil and partially hydrogenated cottonseed oil), fatty acid esters suchas myristyl lactate, stearic acid and palmitic acid esters, cocoa butteror its artificial substitutes, palm oil/palm oil butter, and waxes ormixtures of waxes, which melt at 37° C. or below. In preferredembodiments, the hydrogenated oil is Wecobee M. To be effective in thetablet compositions, the low melting point compound must be edible.

Mono- di- and triglycerides are rarely used as pure components.Hydrogenated vegetable oils, and solid or semisolid fats are usuallymixtures of mono- di- and triglycerides. The melting point of the fat orhydrogenated vegetable oil is characteristic of the mixture and not dueto a single component. Witepsol (brand name by Condea), Supocire (brandname by Gattefosse), and Novata (brand name by Henkel) are commonly usedin manufacturing suppositories, because they melt at body temperature.All are mixtures of triglycerides, monoglycerides and diglycerides.

In preferred embodiments, the low melting point compound comprises fromabout 2.5% to about 20%, by weight, of a tablet composition (e.g., about2.5, 5, 7.5, 10, 12, 14, 15, 16, 18, or 20% (wt/wt)).

The tablets of the present invention also include a water solubleexcipient. As used herein, the term “water soluble excipient” refers toa solid material or mixture of materials that is orally ingestible andreadily dissolves in water. Examples of water soluble excipients includebut are not limited to saccharides, amino acids, and the like.Saccharides are preferred water soluble excipients. Preferably, thesaccharide is a mono-, di- or oligosaccharide. Examples of saccharideswhich may be added to the tablets of the invention may include sorbitol,glucose, dextrose, fructose, maltose and xylitol (all monosaccharides);sucrose, lactose, glucose, galactose and mannitol (all disaccharides).In a specific embodiment, exemplified below, the saccharide is lactose.Preferably, the saccharide is mannitol. Other suitable saccharides areoligosaccharides. Examples of oligosaccharides are dextrates andmaltodextrins. Other water soluble excipients may include amino acidssuch as alanine, arginine, aspartic acid, asparagine, cysteine, glutamicacid, glutamine, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine and valine; glycine and lysine are preferred amino acids.

In preferred embodiments, the water soluble excipient comprises fromabout 25% to about 97.5%, by weight, of a tablet composition. Thepreferred range is about 40% to about 80%. For example, tabletcompositions comprising about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90, 95 or 97.5%, by weight, saccharide are within the scopeof the invention.

As used herein, the term “about” (or “approximately”) means a particularvalue can have a range acceptable to those of skill in the art given thenature of the value and method by which it is determined. In a specificembodiment, the term means within 50% of a given value, preferably with20%, more preferably within 10%, and more preferably still within 5%.

Active Ingredients

As used herein, the term “active ingredient” or “active agent” refers toone or more compounds that have some pharmacological property.Accordingly, more than one type of active ingredient compound may beadded to the tablets of the invention. The tablets of the invention maycomprise any active ingredient which may be orally administered to asubject. Tablets including active ingredients in amounts appropriate forthe desired pharmacological properties at the dosage administration canbe formulated. Any amount of active ingredient that does notsignificantly affect beneficial tablet features, such as hardness,friability and mouthfeel are within the scope of the invention. Placebotablets, which lack an “active ingredient” having a known pharmacologicactivity, are also within the scope of the invention. An “activeingredient” of a placebo can be the water soluble excipient (i.e.,lacking any identifiable “active”), a different water soluble compound,or any non-active compound.

A non-limiting list of acceptable active ingredients may include but isby no means limited to: 1) antipyretic analgesic anti-inflammatoryagents such as indomethacin, aspirin, diclofenac sodium, ketoprofen,ibuprofen, mefenamic acid, dexamethasone, dexamethasone sodium sulfate,hydrocortisone, prednisolone, azulene, phenacetin, isopropylantipyrin,acetaminophen, benzydamine hydrochloride, phenylbutazone, flufenamicacid, mefenamic acid, sodium salicylate, choline salicylate, sasapyrine,clofezone or etodolac; 2) antiulcer agents such as ranitidine,sulpiride, cetraxate hydrochloride, gefarnate, irsogladine maleate,cimetidine, lanitidine hydrochloride, famotidine, nizatidine orroxatidine acetate hydrochloride; 3) coronary vasodilators such asNifedipine, isosorbide dinitrate, diltiazem hydrochloride, trapidil,dipyridamole, dilazep dihydrochloride, methyl2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate,verapamil, nicardipine, nicardipine hydrochloride or verapamilhydrochloride; 4) peripheral vasodialtors such as ifenprodil tartrate,cinepazide maleate, cyclandelate, cinnarizine or pentoxyfyline; 5) oralantibacterial and antifungal agents such as penicillin, ampicillin,amoxicillin, cefalexin, erythromycin ethylsuccinate, bacampicillinhydrochloride, minocycline hydrochloride, chloramphenicol, tetracycline,erythromycin, fluconazole, itraconazole, ketoconazole, miconazole orterbinafine; 6) synthetic antibacterial agents such as nlidixic acid,piromidic acid, pipemidic acid trihydrate, enoxacin, cinoxacin,ofloxacin, norfloxacin, ciprofloxacin hydrochloride, or sulfamethoxazoletrimethoprim; 7) antipasmodics such as popantheline bromide, atropinesulfate, oxapium bromide, timepidium bromide, butylscopolamine bromide,rospium chloride, butropium bromide, N-methylscopolamine methylsulfate,or methyloctatropine bromidebutropium bromide; 8) antitussive,anti-asthmatic agents such as theophylline, aminophylline,methylephedrine hydrochloride, procaterol hydrochloride, trimetoquinolhydrochloride, codeine phosphate, sodium cromoglicate, tranilast,dextromethorphane hydrobromide, dimemorfan phosphate, clobutinolhydrochloride, fominoben hydrochloride, benproperine phosphate,tipepidine hibenzate, eprazinone hydrochloride, clofedanolhydrochloride, ephedrine hydrochloride, noscapine, calbetapentanecitrate, oxeladin tannate, or isoaminile citrate; 9) broncyodilatorssuch as diprophylline, salbutamol sulfate, clorprenaline hydrochloride,formoterol fumarate, orciprenalin sulfate, pirbuterol hydrochloride,hexoprenaline sulfate, bitolterol mesylate, clenbuterol hydrochloride,terbutaline sulfate, mabuterol hydrochloride, fenoterol hydrobromide, ormethoxyphenamine hydrochloride; 10) diuretics such as furosemide,acetazolarmide, trichlormethiazide, methyclothiazide,hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopenthiazide,spironolactone, triamterene, fluorothiazide, piretanide, metruside,ethacrynic acid, azosemide, or clofenamide; 11) muscle relaxants such aschlorphenesin carbamate, tolperisone hydrochloride, eperisonehydrochloride, tizanidine hydrochloride, mephenesin, chlorozoxazone,phenprobamate, methocarbamol, chlormezanone, pridinol mesylate,afloqualone, baclofen, or dantrolene sodium; 12) brain metabolismaltering drugs such as meclofenoxate hydrochloride; 13) minortranquilizers such as oxazolam, diazepam, clotiazepam, medazepam,temazepam, fludiazepam, meprobamate, nitrazepam, or chlordiazepoxide;14) major tranquilizers such as Sulpirid, clocapramine hydrochloride,zotepine, chlorpromazinon, or haloperidol; 15) β-blockers such aspindolol, propranolol hydrochloride, carteolol hydrochloride, metoprololtartrate, labetalol hydrochloride, acebutolol hydrochloride, butetololhydrochloride, alprenolol hydrochloride, arotinolol hydrochloride,oxprenolol hydrochloride, nadolol, bucumolol hydrochloride, indenololhydrochloride, timolol maleate, befunolol hydrochloride, or bupranololhydrochloride; 16) antiarrhythmic agents such as procainamidehydrochloride, disopyramide, ajimaline, quinidine sulfate, aprindinehydrochloride, propafenone hydrochloride, or mexiletine hydrochloride;17) gout suppressants allopurinol, probenecid, colchicine,sulfinpyrazone, benzbromarone, or bucolome; 18) anticoagulants such asticlopidine hydrochloride, dicumarol, or warfarin potassium; 19)antiepileptic agents such as phenytoin, sodium valproate, metharbital,or carbamazepine; 20) antihistaminics such as chlorpheniramine maleate,cremastin fumarate, mequitazine, alimemazine tartrate, or cycloheptazinehydrochloride; 21) antiemetics such as Difenidol hydrochloride,metoclopramide, domperidone, betahistine mesylate, or trimebutinemaleate; 22) hypotensives such as dimethylaminoethyl reserpilinatedihydrochloride, rescinnamine, methyldopa, prazosin hydrochloride,bunazosin hydrochloride, clonidine hydrochloride, budralazine, orurapidin; 23) sympathomimetic agents such as dihydroergotamine mesylate,isoproterenol hydrochloride, or etilefrine hydrochloride; 24)expectorants such as bromhexine hydrochloride, carbocysteine, ethylcysteine hydrochloride, or methyl cysteine hydrochloride; 25) oralantidiabetic agents such as glibenclamide, tolbutamide, or glymidinesodium; 26) circulatory agents such as ubidecarenone or ATP-2Na; 27)iron preparations such as ferrous sulfate or dried ferrous sulfate; 28)vitamins such as vitamin B1, vitamin B2, vitamin B6, vitamin B12,vitamin C, vitamin A, vitamin D, vitamin E, vitamin K or folic acid; 29)pollakiuria remedies such as flavoxate hydrochloride, oxybutyninhydrochloride, terodiline hydrochloride, or4-diethylamino-1,1-dimethyl-2-butynyl (I)-α-cyclohexyl-α-phenylglycolatehydrochloride monohydrate; 30) angiotensin-converting enzyme inhibitorssuch as enalapril maleate, alacepril, or delapril hydrochloride; 31)anti-viral agents such as trisodium phosphonoformate, didanosine,dideoxycytidine, azido-deoxythymidine, didehydro-deoxythymidine,adefovir dipivoxil, abacavir, amprenavir, delavirdine, efavirenz,indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir orstavudine; 32) high potency analgesics such as codeine, dihydrocodeine,hydrocodone, morphine, dilandid, demoral, fentanyl, pentazocine,oxycodone, pentazocine orpropoxyphene; 33) antihistamines such asBrompheniramine maleate and 34) nasal decongestants such asPhenylpropanolamine HCl. Active ingredients in the foregoing list mayalso have beneficial pharmaceutical effects in addition to the onementioned.

Other Tablet Ingredients

The term “tablet” refers to a pharmacological composition in the form ofa small, essentially solid pellet of any shape. Tablet shapes maybecylindrical, spherical, rectangular, capsular or irregular. The term“tablet composition” refers to the substances included in a tablet. A“tablet composition constituent” or “tablet constituent” refers to acompound or substance which is included in a tablet composition. Thesecan include, but are not limited to, the active and any excipients inaddition to the low melting compound and the water soluble excipient. Anexcipient is any ingredient in the tablet except the active, andincludes binders, disintegrants, flavorants, colorants, glidants,souring agents and sweeteners.

For the purposes of the present application, “binder” refers to one ormore ingredients added before or during granulation to form granulesand/or promote cohesive compacts during compression. A “binder compound”or “binder constituent” is a compound or substance which is included inthe binder. Binders of the present invention include, at least, the lowmelting compound.

Additionally, and optionally, other substances commonly used inpharmaceutical formulations can be included such as flavors (e.g.,strawberry aroma, raspberry aroma, cherry flavor, magnasweet 135, keylime flavor, grape flavor trusil art 5-11815, fruit extracts andprosweet), flavor enhancers and sweeteners (e.g., aspartame, sodiumsaccharine, sorbitol, glucose, sucrose), souring agents (e.g. citricacid), dyes or colorants.

The tablet may also contain one or more glidant materials which improvethe flow of the powder blend and minimize tablet weight variation.Glidants such as silicone dioxide may be used in the present invention.

Additionally, the tablets of the invention may include lubricants (e.gmagnesium stearate) to facilitate ejection of the finished tablet fromdies after compression and to prevent tablets from sticking to punchfaces and each other.

Any method of forming a tablet of the invention into a desired shapewhich preserves the essential features thereof are within the scope ofthe invention.

Tablet Formation

A preferred method of forming the tablet compositions of the inventionincludes mixing a fast dissolving granulation, which includes alow-melting point compound and a water soluble excipient, preferably asaccharide. The term “fast dissolving granulation” refers to acomposition of the low melting point compound and the water solubleexcipient prepared for use in manufacture of tablets of the invention. Aportion of the fast dissolving granulation may then be added to theremaining ingredients. However, methods of forming the tablets of theinvention wherein all tablet constituents are combined simultaneously orwherein any combination of tablet constituents are combined separatefrom the other constituents are within the scope of the invention.

Granulation end point can be determined visually (visual inspection). Itcan also be determined using a load cell that measures powerconsumption. Tablet manufacturing and granulation routinely employ bothtechniques.

The tablet compositions of the invention can be formed by meltgranulation which is a preferred method. In particular, the meltgranulation can be performed in a high shear mixer, low shear mixer orfluid bed granulator. An example of high shear mixer is Diosna (this isa brand name by Diosna Dierks & Söhne GmbH). Examples of low shearmixers are various tumbling mixers (e.g., twin shell blenders orV-blender). Examples of fluid bed granulators are Glatt and Aeromaticfluid bed granulators.

There are three ways of manufacturing the granulation:

Melting the low melting point ingredient, then combining it with thewater soluble ingredient(s) in the granulator and mixing until granulesform.

Loading the water soluble excipient in the granulator and spraying themolten low melting point compound on it while mixing.

Combining the two (water soluble component and low melting pointcomponent) and possibly other ingredients and mixing while heating to atemperature around or higher than the melting point of the low meltingpoint component until the granules form.

After the granulation congeals, it may be milled and/or screened.Examples of mills that can be used are CoMill, Stokes Oscillator (theseare brand names). Any mills that are commonly used for milling tabletgranulations may be used.

Melt extrusion can be used to form the fast dissolving granulation. Anexample of an extruder that can be used is Nica (a brand name byNiro-Aeromatic). The low melting point compound and the water solublesaccharide are mixed and heated in a planetary mixer bowl (low shearmixer) that is usually part of the extruder. The soft mass is then fedto the extrusion chamber and forced through small holes or orifices toshape it into thin rods or cylinders. After the extruded materialcongeals it can be milled or spheronized using standard equipment. Inthe spheronization step, the extrudate is dumped onto the spinning plateof the spheronizer and broken up into small cylinders with a lengthequal to their diameter, then rounded by frictional forces (See,International Journal of Pharmaceutics 1995, 116:131-146, especially p.136.).

Spray congealing or prilling can also be used to form the tabletcompositions of the invention. Spray congealing includes atomizingmolten droplets of compositions which include a low melting pointcompound onto a surface or, preferably, other tablet constituents.Equipment that can be used for spray congealing includes spray driers(e.g., Nero spray drier) and a fluid bed coater/granulation with topspray (e.g., Glatt fluid bed coater/granulator). In preferredembodiments, a fast-dissolve granulation is formed wherein, preferably awater soluble excipient, more preferably a saccharide, is suspended in amolten low melting point ingredient and spray congealed. After spraycongealing, the resulting composition is allowed to cool and congeal.Following congealing of the mixture, it is screened or sieved and mixedwith remaining tablet constituents. Spray congealing processes whereinfast-dissolve granulations comprising any combination of low meltingpoint compound and other tablet constituents are melted and spraycongealed onto other tablet constituents are within the scope of thepresent invention. Spray congealing processes wherein all tabletconstituents, including the low-melting point compound, are mixed, thelow melting point compound is melted and the mixture is spray congealedonto a surface are also within the scope of the invention.

After spray congealing, the mixture may be milled and then combined withother tablet constituents. Following formation of the final tabletcomposition, the composition may be further processed to form a tabletshape.

Mixing and milling of tablet constituents during the preparation of atablet composition may be accomplished by any method which causes thecomposition to become mixed to be essentially homogeneous. In preferredembodiments the mixers are high-shear mixers such as the Diosna, CoMillor V-Blender.

Once tablet compositions are prepared, they may be formed into variousshapes. In preferred embodiments, the tablet compositions are pressedinto a shape. This process may comprise placing the tablet compositioninto a form and applying pressure to the composition so as to cause thecomposition to assume the shape of the surface of the form with whichthe composition is in contact. In preferred embodiments, the tablet iscompressed into the form at a pressure which will not exceed about 10kN, preferably less than 5 kN. For example, pressing the tablets at lessthan 1, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 kN iswithin the scope of the invention. The tablets of the inventiongenerally have a hardness of about 3 kP or less; preferably the tabletshave a hardness of about 2 kP or less and more preferably about 1 kP orless. For example, tablets of about 0.05, 0.07, 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1.0, 1.3, 1.6, 1.9, 2.0, 2.1, 2.3, 2.5, 2.7, 2.8 or3.0 or less than 0.1 kP are within the scope of the invention. Hydraulicpresses such as a Carver Press or rotary tablet presses such as theStokes Versa Press are suitable means by which to compress the tabletcompositions of the invention.

Tablets may also be formed by tumbling melt granulation (TMG)essentially as described in Maejima et al, Chemical PharmacologyBulletin.(1997) 45(3): 518-524; which is incorporated herein byreference. Tumbling melt granulation can be used for preparing the meltgranulation. It can be done in a tumbling mixer. The molten low meltingpoint compound is sprayed on the crystalline saccharide and powderedsaccharide in the blender and are mixed until granules form. In thiscase, the low melting ingredient is the binder and the crystallinesaccharide is the seed. An alternative method is to combine the unmeltedlow melting point ingredient, crystalline sugar (e.g. sucrose ormaltose), and water-soluble ingredient in the powder form (e.g.,mannitol or lactose) in the tumbling mixer and mix while heating to themelting point of the low melting point binder or higher. The seed shouldbe crystalline or granular water soluble ingredient (saccharide), e.g.,granular mannitol, crystalline maltose, crystalline sucrose, or anyother sugar. An example of tumbling mixers is the twin-shell blender(V-blender), or any other shape of tumbling mixers. Heating can beachieved by circulating heated air through the chamber of the granulatorand by heating the bottom surface of the chamber. As the seed materialand the powdered tablet constituents circulate in the heated chamber,the low-melting point compound melts and adheres to the seeds. Theunmelted, powdered material adheres to the seed-bound, moltenlow-melting point material. The spherical beads which are formed by thisprocess are then cooled and screen sifted to remove nonadhered powder.

EXAMPLES Example 1 Fast Dissolving Granulations

Compositions of Fast Dissolving Granulations. In these compositions, thewater soluble excipient is a saccharide. As described above, the tabletsof the invention may be formulated by a method wherein a fast dissolvinggranulation, comprising a low melting point compound and a water solubleexcipient, is mixed separately from other tablet constituents. A portionof the fast dissolving granulation may then be combined with the othertablet constituents. In this example, several specific examples of fastdissolving granulations are set forth.

TABLE 1 Fast dissolving granulation formulations. Fast DissolvingGranulation Low Melting Point Saccharide Composition Compound (amount)(amount) 1 Wecobee M hydrogenated mannitol powder (5 Kg) vegetable oil(1 Kg) 2 Gelucire 33/01 mannitol powder (1 Kg) semisynthetic glycerides(200 g) 3 Wecobee M (150 g) crystalline maltose (100 g) mannitol powder(750 g) 4 polyethylene glycol 900 fructose powder (400 g) (100 g)

Fast dissolving granulations 1 and 2 were prepared by heating the lowmelting compound to 50° C. At 50° C., Wecobee M and Gelucire 33/01become molten. The molten material was gradually added to the mannitolpowder in a high shear granulator (Diosna). The granulation was mixed athigh speed. When the granulation end point was reached as determined byvisual inspection, the granulation was allowed to congeal. The congealedgranulation was then milled using a CoMill.

Granulation 3 was granulated by combining melted Wecobee M with themannitol in a high shear mixer (Robot Coupe) and blending until thegranules formed. Granulation 4 was made by combining the melted PEG withfructose powder in a planetary mixer (low shear mixer) and mixing untilthe granules formed. The granulations were allowed to cool, then werescreened.

Example 2 Fast Dissolving Ibuprofen Tablets

The following is an example of a fast dissolving tablet wherein theactive ingredient is ibuprofen.

Ingredient Amount (mg tablet) Coated ibuprofen (active ingredient) 121.9(equivalent to 100 mg ibuprofen) Citric acid (souring agent)  11.0Magnasweet 135 (sweetening agent)  3.9 Aspartame (sweetening agent)  6.5Cherry flavor (flavoring agent)  7.8 Crosscarmellose sodium(disintegrant)  39.0 Silicone dioxide (glidant flow aid)   1.95Magnesium stearate (lubricant)   3.25 Fast dissolving granulation 4457.9 Total 653.2

Ingredients were screened, then mixed in a V-blender. Tablets werecompressed using a hydraulic press (Carver Press) at 600 lb (about 2.7kN). The tablets had a hardness of 0.2-0.5 kP and disintegrated in lessthan 15 seconds.

Example 3 Fast Dissolving Antihistamine/Decongestant Tablets

The following is an example of a fast dissolving tablet comprising theactive ingredients of many common allergy medications,Phenylpropanolamine HCl and Brompheniramine maleate.

Ingredient Amount (mg/tablet) Phenylpropanolamine HCl (activeingredient) 6.25 Brompheniramine maleate (active ingredient) 1.0 Citricacid (souring agent) 6.0 Magnasweet 135 (sweetening agent) 1.80Aspartame (sweetening agent) 4.5 Cherry flavor (flavoring agent) 3.60Crosscarmellose sodium (disintegrant) 21.0 Lecithin (creamy mouthfeel)3.0 Corn Starch (anti-adherent) 30.0 Silicone dioxide (glidant flow aid)3.0 Fast dissolving granulation 4 219.25 Magnesium stearate (lubricant)2.1 Total 301.5

Tablets were compressed on a hydraulic press (Carver Press) atapproximately 3 kN. Tablet hardness was 0.2-0.5 kP and disintegrationtime 10 seconds.

Example 4 Fast Dissolving Ibuprofen Tablets

The following is an example of a fast dissolving tablet wherein theactive ingredient is ibuprofen.

Ingredient Amount (mg/tablet) Coated ibuprofen (active agent) 119.0Citric Acid (souring agent) 20.0 Magnasweet 135 (sweetening agent) 7.5Aspartame (sweetening agent) 7.5 Grape flavor Trusil Art 5-11815(flavoring agent) 5.00 Prosweet (flavor and sweetness enhancer) 5.00Crosscarmellose sodium (enhancer) 20.0 Corn Starch, NF (anti-adherent)40.0 Silicone dioxide (Syloid 244) (glidant flow aid) 5.00 Fastdissolving granulation 1 271 Total 500

Tablets were compressed using a rotary tablet press (Stokes Versa Press)at 3.3.-3.5 kN, resulting in a hardness of 0.2-0.9 kP. In vivodisintegration time was 19 seconds (average of 34 subjects).

Sensory Study: The melt granulation tablets of Example 4 were evaluatedfor in vivo disintegration time and mouthfeel in an in-house sensorystudy. The comparator was Kidtab®, an 80 mg acetaminophen fastdissolving tablet prepared by direct compression. Two other ibuprofenfast dissolving tablets prepared by direct compression were alsoincluded in the study. The study included 34 subjects. The subjects wereasked to record the time for the tablet to completely dissolve in themouth and give scores for mouthfeel attributes and overall liking of theproduct. The melt granulation prototype (based on this invention)performed best on disintegration time (FIG. 6) and mouthfeel attributes(least grittiness (FIG. 7) and least chalkiness (FIG. 8)) and wereranked best on the overall performance by the panelists.

The following table shows the ranking results of the sensory study ondisintegration time and mouthfeel attributes: MG is the melt granulationtablet of the invention. DC1 and DC2 are the two direct compressionprototypes.

Ranking (1 = best, 4 = worst) Prototype/Product Sensory Attribute DC1 MGKidtab DC2 Time to dissolve (seconds) 2 1 4 3 Grittiness 4 1 2 3Chalkiness 3 1 4 2 Overall Preference 4 1 2 3

The tablets of the invention were ranked the highest (1, best) in allfour categories tested (dissolution time, grittiness, chalkiness andoverall performance) against DC1, DC2 and KIDTAB.

As illustrated in FIG. 6, the tablets of the invention exhibitedsuperior fast dissolving characteristics as compared to the directcompression tablets which were also evaluated (DC1, DC2 and KIDTAB); theaverage time for the tablet of the invention (MG) to dissolve was 19seconds wherein the time for DC1, DC2 and KIDTAB to dissolve were about20, 22 and 25 seconds, respectively. The tablets of the invention alsoexhibited a mouthfeel which was superior to the DC1, DC2 and KIDTABtablets. FIGS. 7 and 8 indicate the 34 individuals who participated inthe study perceived a lower level of grittiness and chalkinessassociated with the tablets of the invention as compared to the directcompression tablets (DC1, DC2 and KIDTAB).

Overall preference was also scored (least squares mean from ANOVA) on ascale from 1 (most preferred) to 9 (least preferred). As indicated inFIG. 9, the tablet of the invention scored highest (2.11), followed bythe KIDTAB® (2.29), and the two direct compression tablets (DC2-2.52,DC1-3.05)

Example 5 Fast Dissolving Ibuprofen Tablets

The following is an example of a fast dissolving tablet wherein theactive ingredient is ibuprofen

Ingredient mg/tablet Coated ibuprofen (active agent) 238.0 Citric Acid(souring agent) 17.5 Magnasweet 135 (sweetening agent) 9.75 Aspartame(sweetening agent) 9.75 Key Lime flavor (flavoring agent) 6.50 Vanillapowder (flavoring agent) 0.650 Corn Starch, NF (anti-adherent) 52.0Silicone dioxide (Syloid 244) (glidant/flow aid) 6.50 Sodium stearylfumarate (Pruv) (lubricant) 4.88 Fast dissolving granulation 1 304 Total650

Tablets were compressed using a rotary tablet press (Stokes Versa Press)at 3 kN, resulting in a hardness of 0.35-0.60 kP. In vivo disintegrationtime was 16 seconds.

Example 6 Compressibility and In Vitro Evaluation of Tablets

To compare fast dissolving tablets of the invention with fast dissolvingtablets prepared by direct compression, the following two examples wereprepared.

Melt Granulation Fast Dissolving Tablet:

Ingredient mg/tablet Ibuprofen microcaps 119.0 Citric Acid, anhydrous,fine granular 20.0 Magnasweet 135 7.5 Aspartame (Nutrasweet) 7.5 CherryBerry flavor 4.25 Sweet AM 2.50 Crosscarmellose sodium 20.0 Corn Starch,NF 40.0 Silicone dioxide (Syloid 244) 5.00 Fast dissolve granulation274.25 TOTAL 500 * The granulation is 85.0% Mannitol powder, USP and15.0% Wecobee M (hydrogenated vegetable oil).

Direct Compression Fast Dissolving Tablet:

Ingredient mg/tablet Ibuprofen microcaps 119.0 Citric Acid, anhydrous,fine granular 20.0 Magnasweet 135 7.5 Aspartame (Nutrasweet) 7.5 SweetAM 2.50 Fruit Punch flavor 3.50 Crosscarmellose sodium 20.0 Corn Starch,NF 40.0 Silicone dioxide (Syloid 244) 5.00 Mg Stearate 3.50 Granularmannitol 271.5 TOTAL 500

Melt granulation tablets and direct compression tablets were preparedbased on the same formula, except that granular mannitol was usedinstead of the fast dissolve melt granulation. The compressibility ofthe two tablet formulations (melt granulation and direct compression)were compared. The two blends were compressed at different compressionforces and the resulting tablets were evaluated for hardness and invitro disintegration time. Tablet hardness (crushing strength) wasmeasured using a high resolution texture analyzer (Stable Microsystems)with an acrylic cylindrical probe.

In vitro disintegration was performed in a texture analyzer. A tabletwas held on a net that was then attached to a ¼″ stainless steal ballprobe. The disintegration medium was 5 ml of water in a 50 ml beaker.The height of water was barely enough to submerge the tablet, and thewater temperature was kept at 37±1° C. The texture analyzer wasinstructed to apply a small force (20 g) when the tablet hit the bottomof the beaker. The time for disintegration onset and totaldisintegration time were recorded.

Compressibility: Fast dissolving tablets in general are soft and need tobe blister-packaged directly off the tablet press. The tabletsmanufactured according to the invention can be compressed at very lowcompression forces, which cannot be used with tablets prepared by directcompression or wet granulation. For fast dissolving tablets containing acoated active, it is important to compress at the lowest force possibleso that the coating will not be ruptured under compression. With themelt granulation approach, tablets that are robust enough to withstandpackaging right off the tablet press were obtained using a compressionforce as low as 2 kN, whereas for a similar direct compressionformulation, acceptable tablets could not be obtained at compressionforces below 5 kN (FIG. 1).

Hardness and Friability: Although the melt granulation tablets had alower hardness compared to direct compression tablets that arecompressed at the same force (FIG. 1), the melt granulation tablets weresomewhat pliable and less fragile. As illustrated in FIG. 2, the softestmelt granulation prototype, with a hardness of about 0.2 kP, was able towithstand at least 9 rotations in the friabilator (friability apparatus)before any tablet breaks. At 0.5 kP, these tablets survived 20-30rotations. Direct compression tablets at about 0.45 kP started breakingafter 4 rotations, while the hardest direct compression prototype withabout 0.9 kP hardness only survived 12 rotations. In the same friabilitytest, Kidtab® tablets (marketed fast dissolving tablets prepared bydirect compression) started breaking after 5-10 rotations. The averagehardness of Kidtab tablets was 1.8 kP. Moreover, at the end of the test,the direct compression tablets showed more chipping around the edgesthan melt granulation prototypes. Direct compression tablets withhardness greater than 1 kP were not fast dissolving (took 1 minute ormore to dissolve in the mouth of a subject).

In vitro Disintegration: The onset of disintegration was faster for themelt granulation prototypes compared to direct compression prototypesprepared at the same compression force (FIG. 3). Furthermore, the totaltime for in vitro disintegration was dependent on compression forceregardless of the formulation (FIG. 4). We obtained acceptable tabletsfrom the melt granulation processing low compression force. Directcompression tablets could not be obtained at the same compression force.Therefore, for tablets with similar friability, the melt granulationapproach produced faster disintegration time (FIG. 5).

The melt granulation formulation was less sensitive to small changes incompression force, whereas for the direct compression formulation, bothhardness and onset of disintegration increased sharply with increasingthe compression force (FIGS. 1 and 3).

Example 7 Example of Melt Granulation Tablets with Higher Hardness:

Ingredient mg/tablet Ibuprofen microcaps (encapsulated ibuprofen) 121.9Citric Acid, anhydrous, fine granular 11.0 Magnasweet 135 4.0 Aspartame(Nutrasweet) 6.0 Cherry flavor 6.0 Sweet AM 0.5 Crosscarmellose sodium45.0 Corn Starch, NF 40.0 Silicone dioxide (Syloid 244) 2.50 Fastdissolve granulation 263.1 TOTAL 500 * The granulation is 85.0% Mannitolpowder, USP and 15.0% Wecobee M (hydrogenated vegetable oil).

The granulation is 85.0% Mannitol powder, USP and 15.0% Wecobee M(hydrogenated vegetable oil)

Tablets were compressed on Stokes Versapress. Compression force was notrecorded. Tablet hardness was 1.5 kP. The tablets had a friability ofless than 1.0% after 50 rotations in the friabilator, i.e, lost lessthan 1% of their initial weight and no tablet broke. Mean in vivodisintegration time was 25.8 seconds (12 subjects were asked to take thetablets and record the time it takes for the tablet to completelydissolve without chewing).

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

It is further to be understood that all values are approximate, and areprovided for description.

Patents, patent applications, publications, product descriptions, andprotocols are cited throughout this application, the disclosures ofwhich are incorporated herein by reference in their entireties for allpurposes.

What is claimed:
 1. A tablet comprising a low melting point compoundthat melts or softens at or below 37° C., a water soluble excipient anda pharmacologically active ingredient, wherein the low melting pointcompound comprises from about 2.5% to about 20% (wt/wt) of thecomposition, and wherein the tablet has a hardness of about 1 kilopondor lower.
 2. The tablet of claim 1, wherein the water soluble excipientcomprises about 25% to about 97.5% (wt/wt) of the tablet.
 3. The tabletof claim 1 wherein the water soluble excipient comprises about 40% toabout 85% (wt/wt) of the tablet.
 4. The tablet of claim 1 wherein thewater soluble excipient is a saccharide.
 5. The tablet of claim 4wherein the saccharide is one or more substances selected from the groupconsisting of maltose, fructose, sucrose, lactose, glucose, galactose,xylitol, sorbitol, dextrates, maltodextrins and mannitol.
 6. The tabletof claim 1 wherein the water soluble excipient is an amino acid.
 7. Thetablet of claim 6 wherein the amino acid is one or more compoundsselected from the group consisting of glycine and lysine.
 8. The tabletof claim 1 further comprising one or more components selected from thegroup consisting of a disintegrant, a colorant, a sweetener, a souringagent, a glidant, a binder, a lubricant and a flavorant.
 9. The tabletof claim 1 wherein the low melting point compound is one or morecompounds selected from the group consisting of hydrogenated oil,polyethylene glycol, low melting point triglycerides, low melting pointdiglycerides, low melting point monoglycerides, synthetic glycerides,fatty acid esters, semisynthetic glycerides, partially hydrogenated oil,palm oil, palm butter, wax and cocoa butter.
 10. The tablet of claim 9wherein the low melting point compound comprises a mixture of amonoglyceride, a diglyceride and a triglyceride.
 11. The tablet of claim9 wherein the low melting point compound is a partially hydrogenatedoil.
 12. The tablet of claim 9 wherein the low melting point compound isa hydrogenated oil.
 13. The tablet of claim 9 wherein the low meltingpoint compound is a fatty acid ester and the fatty acid ester is one ormore compounds selected from the group consisting of stearic acid ester,palmitic acid ester and myristyl lactate ester.
 14. A method ofproducing a tablet composition, which method comprises combining apharmacologically active agent with a fast dissolving granulation,wherein the fast dissolving granulation comprises a low melting pointcompound that melts or softens at or below 37° C. and a water solubleexcipient, and wherein the low melting point compound comprises fromabout 2.5% to about 20% (wt/wt) of the tablet composition, and whereinthe tablet ban hardness of about 3 kilopond or lower.
 15. The method ofclaim 14, which further comprises adding one or more components selectedfrom the group consisting of a disintegrant, a colorant, a sweetener, alubricant, a souring agent, a glidant, a binder and a flavorant.
 16. Themethod of claim 14, which further comprises molding the tabletcomposition into a tablet form.
 17. The method of 14, wherein the fastdissolving granulation is prepared by high sheer granulation.
 18. Themethod of claim 17 wherein the low melting point compound is molten. 19.The method of claim 18 wherein the fast dissolving granulation isprepared by spraying the molten low melting point compound onto thewater soluble excipient and allowing the resulting composition tocongeal.
 20. The method of claim 18 wherein the fast dissolvinggranulation is prepared by suspending the water soluble excipient inmolten low melting point compound and spray congealing the resultingcomposition.
 21. The method of claim 18 wherein the fast dissolvinggranulation is made by a method comprising extruding the compositioncomprising the active agent and the fast dissolving granulation througha nozzle and allowing the resulting composition to congeal.
 22. Themethod of claim 18 wherein the water soluble excipient is one or moresaccharides selected from the group consisting of maltose, fructose,sucrose, lactose, glucose, galactose, xylitol, sorbitol, and mannitol.23. The method of claim 18 wherein the low melting point compound is oneor more compounds selected from the group consisting of hydrogenatedoil, polyethylene glycol, low melting point triglycerides, low meltingpoint diglycerides, low melting point monoglycerides, syntheticglycerides, fatty acid esters, semisynthetic glycerides, partiallyhydrogenated oil, palm oil, palm butter, wax and cocoa butter.
 24. Themethod of claim 18 which comprises congealing a mixture comprisingmolten low melting point compound and the water soluble excipient. 25.The method of claim 24, which further comprises granulating thecongealed mixture by a method selected from the group consisting ofsifting the congealed mixture through a screen and milling the congealedmixture.
 26. The method of claim 25 which further comprises molding thegranulated mixture into a tablet shape.
 27. A tablet comprising a lowmelting point compound that melts or softens at or below 37° C., a watersoluble excipient and an active ingredient, wherein the low meltingpoint compound comprises from about 2.5% to about 20% (wt/wt) of thecomposition, and wherein the tablet disintegrates in an oral cavity in10 to 30 seconds.
 28. The tablet of claim 27 comprising a hardness ofabout 3 kilopond or less.
 29. The tablet of claim 28 comprising ahardness of about 2 kilopond or less.
 30. The tablet of claim 29comprising a hardness of about 1 kilopond or less.
 31. The tablet ofclaim 27, wherein the water soluble excipient comprises about 25% toabout 97.5% (wt/wt) of the tablet.
 32. The tablet of claim 27 whereinthe water soluble excipient comprises about 40% to about 85% (wt/wt) ofthe tablet.
 33. The tablet of claim 27 wherein the water solubleexcipient is a saccharide.
 34. The tablet of claim 33 wherein thesaccharide is one or more substances selected from the group consistingof maltose, fructose, sucrose, lactose, glucose, galactose, xylitol,sorbitol, dextrates, maltodextrins and mannitol.
 35. The tablet of claim27 wherein the water soluble excipient is an amino acid.
 36. The tabletof claim 35 wherein the water soluble excipient is an amino acid and theamino acid is one or more compounds selected from the group consistingof glycine and lysine.
 37. The tablet of claim further comprising one ormore components selected from the group consisting of a disintegrant, acolorant, a sweetener, a souring agent, a glidant, a binder, a lubricantand a flavorant.
 38. The tablet of claim 27 wherein the low meltingpoint compound is one or more compounds selected from the groupconsisting of hydrogenated oil, polyethylene glycol, low melting pointtriglycerides, low melting point diglycerides, low melting pointmonoglycerides, synthetic glycerides, fatty acid esters, semisyntheticglycerides, partially hydrogenated oil, palm oil, palm butter, wax andcocoa butter.
 39. The tablet of claim 37 wherein the low melting pointcompound comprises a mixture of a monoglyceride, a diglyceride and atriglyceride.
 40. The tablet of claim 38 wherein the low melting pointcompound is a partially hydrogenated oil and wherein the partiallyhydrogenated oil is one or more substances selected from the groupconsisting of partially hydrogenated palm kern oil and partiallyhydrogenated cotton seed oil.
 41. The tablet of claim 38 wherein the lowmelting point compound is a hydrogenated oil.
 42. The tablet of claim 38wherein the low melting point compound is a fatty avid ester and thefatty avid ester is one or more compounds selected from the groupconsisting of stearic acid ester, palmitic acid eater and myristyllactate ester.
 43. The tablet of claim 11, wherein the partiallyhydrogenated oil is partially hydrogenated palm kern oil and partiallyhydrogenated cotton seed oil.
 44. The method of claim 14, wherein thewater soluble excipient is one saccharide.